The present invention is useful for the treatment of many disorders, particularly tissue or organ failure (such as kidney or liver failure), corneal disorders, gastrointestinal disorders, and dermatological disorders. At present, many of the methods of therapy for these disorders involve invasive surgical methods, such as organ transplant in the case of extreme tissue damage. Organ transplantation involves many risks, such as complications resulting from the anesthesia and surgical procedures, side effects from medications, such as cyclosporin, which help prevent organ rejection, and the risks of blood borne pathogens or shock if transfusions are needed. Moreover, organ transplantation is very costly. The present invention functions to treat disorders with a therapy that has minimal risk of complications, low cost, and no serious side-effects.
The present invention concerns useful therapeutic formulations having L-amino acids present in molar ratios corresponding to either (1) the ratio of the amino constituents in normal tissue or normal organs, or (2) the constituents found in a medicinal compound useful for treating a medical disorder. Furthermore, Applicants have discovered that relatively low amounts of this therapeutic formulation comprised of L-amino acids, such as a daily intake of about 10 grams or less for an adult, are sufficient for therapeutic effect. The invention can be used with many medical disorders, preferably to avert the need for organ transplants, to treat the biological rejection of a transplanted organ, or prophylactically after transplantation before rejection occurs to reduce the risk of organ rejection. In one embodiment, the therapeutic formulations of the invention are administered for pre-operative optimal care where considerations for surgery have not been finalized. In one embodiment, the therapeutic formulation components simulate the chemical components in cyclosporin.
Elemental feedings containing free amino acids are known as substitutes for milk allergies or milk intolerance, such as in infantile asthma, eczema, or colic. The following articles disclose such uses, all of which are incorporated in their entirety herein by reference: Beyond hydrolysates: Use of L-amino acid formula in resistant dietary protein-induced: intestinal disease in infants, Lake, A. M., J. Pediatrics, 131:658-660 (1997); Intolerance to protein hydrolsate infant formulas: An under-recognized cause of gastrointestinal symptoms in infants, Mack, D. R., Antonson, D. L., Corkins, M. R., Perry, D., and Kruger, R., J. Pediatrics, 131:741-744 (1997); Allergy to extensively hydrolyzed cow milk proteins in infants: Identification and treatment with an amino acid-based formula, DeBoissieu, D., Matarazzo, P., and Dupont, C., J Pediatrics, 131:741-744 (1997); and Efficacy and safety of hydrolyzed cow milk and amino acid-derived formula in infants with cow milk allergy, Solauri, E., Sutas, Y., Makinen-Kilgunen, S., Oja, S. S., Isosomppi, R. and Turjanmaa, K., J Pediatrics, 131:550-557 (1997). Elemental feedings are also known to be useful for treatment of gastrointestinal conditions, such as Crohn's disease (regional ileitis), as noted in the following article, which is incorporated herein in its entirety by reference: Treatment of active Crohn's disease by exclusion diet: East Anglian multicentre controlled trial, Riordan, A. M., Hunter, J. O., Cowan, R. E., Crampton, J. R., Davidson, A. R., Dickinson, R. J., Dronfield, M. W., Ellows, I. W., Hishon, S, and Kerrigan, G. N., et al., Lancet, 342 (8880):1131-1134 (Nov. 6, 1993). In the present invention, much smaller dosages of L-amino acids are used than are found in elemental feedings. Furthermore, the inventive compositions contain specific molar ratios of L-amino acids for a given disease or to mimic therapy with a given medicament.
The present invention is particularly useful for the medical treatment of congenital biliary atresia, which is the most common cause for pediatric liver transplantation. Congenital biliary atresia has been a fatal disease if not treated surgically with liver transplantation and the Kasai procedure. Past research suggests that congenital biliary atresia is caused by the following: (1) hypersensitivity immunopathy; (2) viral infection-hepatic; and (3) inflammation due to (1) and (2). Eosinophiles present in early stages are suggestive of possible hypersensitivity. In the article entitled Contribution of Hepatic Parenchymal and Nonparenchymal Cells to Hepatic Fibrogenesis in Biliary Atresia, Ramm, Grant A., Nair, Visalini G., Bridle, Kim R., and Shepherd, Ross W., American Journal of Pathology, 13(2)L 27-35 (August 1998), which is hereby incorporated herein in its entirety by reference, it is disclosed that extrahepatic congenital biliary atresia is a severe neonatal liver disease resulting from a sclerosing cholangiopathy of unknown etiology. Although biliary obstruction may be surgically improved by a “Kasai” hepatoportoenterostomy, most patients still develop progressive hepatic fibrosis and cirrhosis. Although the source of increased collagen deposition is unclear, an article entitled Prognostic value of serum procollagen III peptide and type IV collagen in patients with congenital biliary atresia, Kobayashi, H., Mayano, T., Horikoshi, K., and Tokita, A., J. of Ped. Surgery, 33(1):112-114 (January 1998), which is hereby incorporated herein in its entirety by reference, discloses that progressive hepatic fibrosis, in spite of a successful Kasai procedure, is a major problem in patients with congenital biliary atresia. N-terminal procollagen-III peptide (PIIP) (which is a marker of fibrogenesis, and therefore, of ongoing inflammation), and type IV collagen (found in basement membrane extracellular matrix), were measured in patients with congenital biliary atresia to determine their potential as prognostic markers.
Long-term follow-up of patients with congenital biliary atresia successfully treated with hepatic portoenterostomy: The importance of sequential treatment, Lopez-Santamaria, M., Gamez, M., Marcia, J., Diez-Pardo, J., Diaz, M., Leal, N., Lobato, R., Martinez, L., Hierro, L., Camarena, C., De La Vega, A., Frauca, E., Jara, P., Barrocal, T., Prieto, C., Coretes, P., and Tovar, J., Ped. Surgery International 13(5-6):327 (July 1998), which is hereby incorporated herein in its entirety by reference, discloses long-term follow-up of patients with congenital biliary atresia who have been treated with hepatic portoenterostomy. As to the importance of sequential treatment, the authors concluded that the natural outcome of extrahepatic biliary atresia is toward fibrosis, and cirrhosis, even in those cases successfully treated with hepatic portoenterostomy (HPE).
Urinary 7alpha-hydroxy-3-oxochol-4-en-24-oic and 3-oxochola-4,6-dien-24-oic acids in infants with cholestasis, Kimura, A., Suzuki, M., Murai, T., Kurosawa, T., Tohma, M., Sata, M., Inoue, T., Hoshiyama, A., Nakashima, E., Yamashita, Y., Fujisawa, T., and Kate, H., J. of Hepatology, 28(2):270-279 (February 1998), which is hereby incorporated herein in its entirety by reference, discloses that urinary 3-oxo-delta4 bile acids have been detected in infants who ultimately died of liver disease. The results reported in this article suggest that an increase in the 7 alpha-hydroxy-3-oxochol4-en-24-oic acid and 3-oxochola-4,6-dien-24-oic acid in the urine of patients with hepatobiliary disease indicates a poor prognosis.
The first cooperative living-related donor liver transplantation performed by two separate institution teams: The Kanaqawa Liver Transplantation Program, Ohhama, Y., Shinkai, M., Fujita, S., Nishi, T., Yamamoto, H., Torigai, K., Takemiya, S., Sugimasa, Y., Akaike, M., and Tanabe, H., Surgery Today, 28(2):173-177 (1998), which is hereby incorporated herein in its entirety by reference, is a study of living-related donor liver transplantations. The study involves five children with congenital biliary atresia who were given partial liver grafts obtained from their mothers in January, 1995.
Portal vein reconstruction in pediatric liver transplantation from living donors, Saad, S., Tanaka, K., Inomata, Y., Uamoto, S., Ozaki, N., Okajima, H., Egawa, H., and Yamacka, Y., Annals of Surgery, 227(2):275-281 (February 1998), which is hereby incorporated herein in its entirety by reference, discloses that in living related partial liver transplantations, portal vein anastomosis to the confluence, with or without the use of vein grafts, is an optional alternative to end-to-end reconstruction, especially in small children.
Soluble ICAM-1 (Sicam-1) in congenital biliary atresia, Minnick, K. E., Kreisberg, R., and Dillon, P. W., J. of Surgical Research, 76(1), 53-56 (April 1998), which is hereby incorporated herein in its entirety by reference, discloses that SICAM-1 (Soluble Intercellular Adhesion Molecule-1) is markedly elevated in congenital biliary atresia, reflecting the immunopathology of the disease process, but it does not appear to correlate with markers of liver function. SICAM-1 may be useful in assessing the effects of immunomodulatory therapy.
Diverse morphology of biliary atresia in an animal model, Petersen, C., Grasshoff, S., and Luciano, L., Journal of Hepatology, 28(4):603-607 (April 1998), which is hereby incorporated herein in its entirety by reference, discloses diverse morphology of congenital biliary atresia in an animal model and relates the findings to congenital biliary atresia in children. Extrahepatic congenital biliary atresia can be simulated in Balb/c-mice which have been infected with a rotavirus. Irreversible occlusion of the common bile duct is the result of an inflammatory process of the whole biliary tract. The observations in this animal model are analogous to observations of extrahepatic congenital biliary atresia in newborn children. This original model can be used to help determine the minimal therapeutic dose required of the present invention per animal weight of this nutrient therapy (similar concept to toxicologic studies for minimal lethal dosage). These studies suggest that most types of extrahepatic congenital biliary atresia in children can be mimicked in an animal model.
Neurodevelopmental outcome of young children with extrahepatic congenital biliary atresia 1 year after liver transplantation, Wayman, K. I., Cox, K. L., and Esquivel, C. O., Journal of Pediatrics, 131(6):894-898 (December 1997), which is hereby incorporated herein in its entirety by reference, stresses that urgent nutritional therapy is a preventive measure for development delay.
A case series of transplant recipients who despite immunosuppression developed inflammatory bowel disease, Riley, T. R., Schoen, R. E., Lee, R. G., and Rakela, J., American J. of Gastroenterology, 92(2):279-282 (February 1997), which is hereby incorporated herein in its entirety by reference, discloses a small number of patients who developed inflammatory bowel disease (IBD), including Crohn's Disease, after solid organ transplantation, one of which had pre-transplantation diagnosis of congenital biliary atresia, despite use of immunosuppressive therapy.
Congenital biliary atresia is similar to infantile asthma; the asthma and associated inflammation and edema occur in the tracheobronchial tree, whereas in congenital biliary atresia, the shock organ and associated inflammation and edema occur in the biliary tree. In a preferred embodiment, the method and composition of the present invention treats congenital biliary atresia without resulting in cirrhosis or inflammatory bowel disease, two common ailments suffered by children having received conventional therapy for congenital biliary atresia.